Ultrasound-enhanced delivery of materials into and through the skin

ABSTRACT

A method for enhancing the permeability of the skin or other biological membrane to a material such as a drug is disclosed. In the method, the drug is delivered in conjunction with ultrasound having a frequency of above about 10 MHz. The method may also be used in conjunction with chemical permeation enhancers and/or with iontophoresis.

This application is a division, of application Ser. No. 07/484,560filed, Feb. 23, 1990, now U.S. Pat. No. 5,115,805.

TECHNICAL FIELD

This invention relates generally to the field of drug delivery. Moreparticularly, the invention relates to a method of enhancing the rate ofpermeation of topically, transmucosally or transdermally appliedmaterials using high frequency ultrasound.

BACKGROUND

The delivery of drugs through the skin ("transdermal drug delivery" or"TDD") provides many advantages; primarily, such a means of delivery isa comfortable, convenient and non-invasive way of administering drugs.The variable rates of absorption and metabolism encountered in oraltreatment are avoided, and other inherent inconveniences--e.g.,gastrointestinal irritation and the like--are eliminated as well.Transdermal drug delivery also makes possible a high degree of controlover blood concentrations of any particular drug.

Skin is a structurally complex, relatively impermeable membrane.Molecules moving from the environment into and through intact skin mustfirst penetrate the stratum corneum and any material on its surface.They must then penetrate the viable epidermis, the papillary dermis, andthe capillary walls into the blood stream or lymph channels. To be soabsorbed, molecules must overcome a different resistance to penetrationin each type of tissue. Transport across the skin membrane is thus acomplex phenomenon. However, it is the stratum corneum, a layerapproximately 5-15 micrometers thick over most of the body, whichpresents the primary barrier to absorption of topical compositions ortransdermally administered drugs. It is believed to be the high degreeof keratinization within its cells as well as their dense packing andcementation by ordered, semicrystalline lipids which create in manycases a substantially impermeable barrier to drug penetration.Applicability of transdermal drug delivery is thus presently limited,because the skin is such an excellent barrier to the ingress oftopically applied materials. For example, many of the new peptides andproteins now produced as a result of the biotechnology revolution cannotbe delivered across the skin in sufficient quantities due to theirnaturally low rates of skin permeability.

Various methods have been used to increase skin permeability, and inparticular to increase the permeability of the stratum corneum (i.e., soas to achieve enhanced penetration, through the skin, of the drug to beadministered transdermally). The primary focus has been on the use ofchemical enhancers, i.e., wherein drug is coadministered with apenetration enhancing agent (or "permeation enhancer"). While suchcompounds are effective through the skin, there are drawbacks with manypermeation enhancers which limit their use. For example, many permeationenhancers are associated with deleterious effects on the skin (e.g.,irritation). In addition, control of drug delivery with chemicalenhancement can be quite difficult.

Iontophoresis has also been used to increase the permeability of skin todrugs, and involves (1) the application of an external electric field,and (2) topical delivery of an ionized form of drug (or of a neutraldrug carried with the water flux associated with ion transport, i.e.,via "electroosmosis"). While permeation enhancement via iontophoresishas, as with chemical enhancers, been effective, there are problems withcontrol of drug delivery and the degree of irreversible skin damageinduced by the transmembrane passage of current.

The presently disclosed and claimed method involves the use ofultrasound to decrease the barrier function of the stratum corneum andthus increase the rate at which a drug may be delivered through theskin. "Ultrasound" is defined as mechanical pressure waves withfrequencies above 20,000 Hz (see, e.g., H. Lutz et al., Manual ofUltrasound: 1. Basic Physical and Technical Principles (Berlin:Springer-Verlag, 1984)).

As discussed by P. Tyle et al. in Pharmaceutical Research 6(5):355-361(1989), drug penetration achieved via "sonophoresis" (the movement ofdrugs through skin under the influence of an ultrasonic perturbation;see D. M. Skauen and G. M. Zentner, Int. J. Pharmaceutics 20:235-245(1984)), is believed to result from thermal, mechanical and chemicalalteration of biological tissues by the applied ultrasonic waves. Unlikeiontophoresis, the risk of skin damage appears to be low.

Applications of ultrasound to drug delivery have been discussed in theliterature. See, for example: P. Tyle et al., supra (which provides anoverview of sonophoresis); S. Miyazaki et al., J. Pharm. Pharmacol.40:716-717 (1988) (controlled release of insulin from a polymer implantusing ultrasound); J. Kost et al., Proceed. Intern. Symp. Control. Rel.Bioact. Mater. 16(141):294-295 (1989) (overview of the effect ofultrasound on the permeability of human skin and synthetic membranes);H. Benson et al., Physical Therapy 69(2):113-118 (1989) (effect ofultrasound on the percurtaneous absorption of benzydamine); E. Novak,arch. Phys. Medicine & Rehab. 45:231-232 (1964) (enhanced penetration oflidocaine through intact skin using ultrasound); J. E. Griffin et al.,Amer. J. Phys. Medicine 44(1):20-25 (1965) (ultrasonic penetration ofcortisol into pig tissue); J. E. Griffin et al., J. Amer. Phys. TherapyAssoc. 46:18-26 (1966) (overview of the use of ultrasound energy in drugtherapy); J. E. Griffin et al., Phys. Therapy 47(7):594-601 (1967)(ultrasound penetration of hydrocortisone): J. E. Griffin et al., Phys.Therapy 48(12):1,336-1,344 (1968) (ultrasound penetration of cortisolinto pig tissue); J. E. Griffin et al., Amer. J. Phys. Medicine51(2):62-72 (1972) (same); J. C. McElnay, Int. J. Pharmaceutics40:105-110 (1987) (the effect of ultrasound on the percutaneousabsorption of fluocinolone acetonide); and C. Escoffier et al., Bioeng.Skin 2:87-94 (1986) (in vitro study of the velocity of ultrasound inskin).

In addition to the aforementioned art, U.S. Pat. Nos. 4,767,402 and4,780,212 to Kost et al. relate specifically to the sue of specificfrequencies of ultrasound to enhance the rate of permeation of a drugthrough human skin or through a synthetic membrane.

While the application of ultrasound in conjunction with drug delivery isthus known, results have for the most part been disappointing, i.e.,enhancement of skin permeability has been relatively low.

SUMMARY OF THE INVENTION

The present invention provides a novel method for enhancing the rate ofpermeation of a given material through a selected intact area of anindividual's body surface. The method comprises contacting the selectedintact area with the material and applying ultrasound to the contactedarea. The ultrasound preferably has a frequency of above about 10 MHz,and is continued at an intensity and for a period of time sufficient toenhance the rate of permeation of the material into and through the bodysurface. The ultrasound can also be used to pretreat the selected areaof the body surface in preparation for drug delivery, or for diagnosticpurposes, i.e., to enable non-invasive sampling of physiologic materialbeneath the skin or body surface.

In addition to enhancing the rate of permeation of a material, thepresent invention involves increasing the permeability of a biologicalmembrane such as the stratum corneum by applying ultrasound having afrequency of above about 10 MHz to the membrane at an intensity and fora period of time sufficient to give rise to increased permeability ofthe membrane. Once the permeability of the membrane has been increased,it is possible to apply a material thereto and obtain an increased rateof flow of the material through the membrane.

It is accordingly a primary object of the invention to address theaforementioned deficiencies of the prior art by providing a method ofenhancing the permeability of biological membranes and thus allow for anincreased rate of delivery of material therethrough.

It is another object of the invention to provide such a method which iseffective with or without chemical permeation enhancers.

It is still another object of the invention to minimize lag time in sucha method and provide a relatively short total treatment time.

It is yet another object of the invention to provide such a method inwhich drug delivery is effected using ultrasound.

It is a further object of the invention to enable sampling of tissuebeneath the skin or other body surface by application of high frequency(>10 MHz) ultrasound thereto.

A further feature of the invention is that it preferably involvesultrasound of a frequency greater than about 10 MHz.

Additional objects, advantages and novel features of the invention willbe set forth in part i the description which follows, and in part willbecome apparent to those skilled in the art upon examination of thefollowing, or may be learned by practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B and 1C are theoretical plots of energy dissipation withinthe skin barrier versus frequency of applied ultrasound.

FIGS. 2, 3 and 4 are graphic representations of the amount of salicylicacid recovered from the stratum corneum after ultrasound treatment atdifferent frequencies. FIGS. 5 and 6 represent the results ofexperiments similar to those summarized in FIGS. 2, 3 and 4, but with ashorter treatment time.

FIGS. 7, 8, 9 and 10 are plots of enhancement versus "tape-stripnumber," as described in the Example.

FIG. 11 illustrates the effect of ultrasound on the systemicavailability of salicylic acid following topical application.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Before the present method of enhancing the rate of permeation of amaterial through a biological membrane and enhancing the permeability ofmembranes using ultrasound are disclosed and described, it is to beunderstood that this invention is not limited to the particular processsteps and materials disclosed herein as such process steps and materialsmay, of course, vary. It is also to be understood that the terminologyused herein is used for purpose of describing particular embodimentsonly and is not intended to be limiting since the scope of the presentinvention will be limited only by the appended claims.

It must be noted that as used in this specification and the appendedclaims, the singular forms "a", "an" and "the" include plural referenceunless the context clearly dictates otherwise. Thus, for example,reference to "a drug" includes mixtures of drugs and theirpharmaceutically acceptable salts, reference to "an ultrasound device"includes one or more ultrasound devices of the type necessary forcarrying out the present invention, and reference to "the method ofadministration" includes one or more different methods of administrationknown to those skilled in the art or which will become known to thoseskilled in the art upon reading this disclosure.

In one aspect of the invention, a method is provided for enhancing thepermeation of a given material such as a drug, pharmacologically activeagent, or diagnostic agent into and/or through a biological membrane onan individual's body surface, which method comprises: (a) contacting themembrane with the chosen material in a pharmacologically acceptablecarrier medium; and (b) applying ultrasound of an intensity and for atreatment time effective to produce delivery of the material through themembrane. The material is preferably a drug and it is preferable toobtain a desired blood level of the drug in the individual. Theultrasound is of a frequency and intensity effective to increase thepermeability of the selected area to the applied drug over that whichwould be obtained without ultrasound. The ultrasound preferably has afrequency of more than 10 MHz, and may be applied either continuously orpulsed, preferably continuously. The ultrasound may be applied to theskin either before or after application of the drug medium so long asadministration of the ultrasound and the drug medium is relativelysimultaneous, i.e., the ultrasound is applied within about 6, morepreferably within about 4, most preferably within about 2 minutes ofdrug application.

The invention is useful for achieving transdermal permeation ofpharmacologically active agents which otherwise would be quite difficultto deliver through the skin or other body surface. For example,proteinaceous drugs and other high molecular weight pharmacologicallyactive agents are ideal candidates for transdermal, transmucosal ortopical delivery using the presently disclosed method. In an alternativeembodiment, agents useful of diagnostic purposes may also be deliveredinto and/or through the body surface using the present method.

The invention is also useful as a non-invasive diagnostic technique,i.e., in enabling the sampling of physiologic material from beneath theskin or other body surface and into a collection (and/or evaluation)chamber.

The present invention will employ, unless otherwise indicated,conventional pharmaceutical methodology and more specificallyconventional methodology used in connection with transdermal delivery ofpharmaceutically active compounds and enhancers.

In describing the present invention, the following terminology will beused in accordance with the definitions set out below.

A "biological membrane" is intended to mean a membrane material presentwithin a living organism which separates one area of the organism fromanother and, more specifically, which separates the organism from itsouter environment. Skin and mucous membranes are thus included.

"Penetration enhancement" or "permeation enhancement" as used hereinrelates to an increase in the permeability of skin to a material such asa pharmacologically active agent, i.e., so as to increase the rate atwhich the material permeates into and through the skin. The presentinvention involves enhancement of permeation through the use ofultrasound, and, in particular, through the use of ultrasound having afrequency of greater than 10 MHz.

"Transdermal" (or "percutaneous") shall mean passage of a material intoand through the skin to achieve effective therapeutic blood levels ordeep tissue therapeutic levels. While the invention is described hereinprimarily in terms of "transdermal" administration, it will beappreciated by those skilled in the art that the presently disclosed andclaimed method also encompasses the "transmucosal" and "topical"administration of drugs using ultrasound. "Transmucosal" is intended tomean passage of any given material through a mucosal membrane of aliving organism and more specifically shall refer to the passage of amaterial from the outside environment of the organism, through a mucousmembrane and into the organism. ÷Transmucosal" administration thusincludes delivery of drugs through either nasal or buccal tissue. By"topical" administration is meant local administration of a topicalpharmacologically active agent to the skin as in, for example, thetreatment of various skin disorders or the administration of a localanaesthetic. "Topical" delivery can involve penetration of a drug intothe skin but not through it, i.e., topical administration does notinvolve actual passage of a drug into the bloodstream.

"Carriers" or "vehicles" as used herein refer to carrier materialswithout pharmacological activity which are suitable for administrationwith other pharmaceutically active materials, and include any suchmaterials known in the art, e.g., any liquid, gel, solvent, liquiddiluent, solubilizer, or the like, which is nontoxic and which does notinteract with the drug to be administered in a deleterious manner.Examples of suitable carriers for use herein include water, mineral oil,silicone, inorganic gels, aqueous emulsions, liquid sugars, waxes,petroleum jelly, and a variety of other oils and polymeric materials.

By the term "pharmacologically active agent" or "drug" as used herein ismeant any chemical material or compound suitable for transdermal ortransmucosal administration which can either (1) have a prophylacticeffect on the organism and prevent an undesired biological effect suchas preventing an infection, (2) alleviates a condition caused by adisease such as alleviating pain caused as a result of a disease, or (3)either alleviates or completely eliminates the disease from theorganism. The effect of the agent may be local, such as providing for alocal anaesthetic effect or it may be systemic. Such substances includethe broad classes of compounds normally delivered through body surfacesand membranes, including skin. In general, this includes:anti-infectives such as antibiotics and antiviral agents; analgesics andanalgesic combinations; anorexics; antihelminthics; antiarthritics;antiasthmatic agents; anticonvulsants; antidepressants; antidiabeticagents; antidiarrheals; antihistamines; antiinflammatory agents;antimigraine preparations; antinauseants; antineoplastics;antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics;antispasmodics; anticholinergics; sympathomimetics; xanthinederivatives; cardiovascular preparations including potassium and calciumchannel blockers, beta-blockers, and antiarrhythmics; antihypertensives;diuretics; vasodilators including general coronary, peripheral andcerebral; central nervous system stimulants; cough and coldpreparations, including decongestants; hormones such as estradiol andother steroids, including corticosteroids; hypnotics;immunosuppressives; muscle relaxants; parasympatholytics;psychostimulants; sedatives; and tranquilizers. By the method of thepresent invention, both ionized and nonionzed drugs may be delivered, ascan drugs of either high or low molecular weight.

Proteinaceous and polypeptide drugs represent a preferred class of drugsfor use in conjunction with the presently disclosed and claimedinvention. Such drugs cannon generally be administered orally in thatthey are often destroyed in the G.I. tract or metabolized in the liver.Further, due to the high molecular weight of most polypeptide drugs,conventional transdermal delivery systems are not generally effective.It is also desirable to use the method of the invention in conjunctionwith drugs to which the permeability of the skin is relatively low, orwhich give rise to a long lag-time (application of ultrasound asdescribed herein has been found to significantly reduce the lag-timeinvolved with the transdermal administration of most drugs).

By a "therapeutically effective" amount of a pharmacologically activeagent is meant a nontoxic but sufficient amount of a compound to providethe desired therapeutic effect. The desired therapeutic effect may be aprophylactic effect, in preventing a disease, an effect which alleviatesa system of the disease, or a curative effect which either eliminates oraids in the elimination of the disease.

As noted above, the present invention is a method for enhancing the rateof permeation of a drug through an intact area of an individual's bodysurface, preferably the human skin. The method involves transdermaladministration of a selected drug in conjunction with ultrasound.Ultrasound causes thermal, mechanical and chemical alterations ofbiological tissue, thereby enhancing the rate of permeation of a givenmaterial therethrough.

While not wishing to be bound by theory, applicants propose that the useof higher frequency ultrasound as disclosed herein specifically enhancesthe permeation of the drug through the outer layer of skin, i.e., thestratum corneum, by causing momentary and reversible perturbationswithin (and thus short-term, reversible reduction in the barrierfunction of) the layer of the stratum corneum. It will be appreciated bythose skilled in the art of transdermal drug delivery that a number offactors related to the present method will vary with the drug to beadministered, the disease or injury to be treated, the age of theselected individual, the location of the skin to which the drug isapplied, and the like.

As noted above, "ultrasound" is ultrasonic radiation of a frequencyabove 20,000 Hz. As may be deduced from the literature cited above,ultrasound used for most medical purposes typically employs frequenciesranging from 1.6 to about 10 MHz. The present invention, by contrast,employs ultrasound frequencies of greater than about 10 MHz, preferablyin the range of about 15 to 50 MHz, most preferably in the range ofabout 15 to 25 MHz. It should be emphasized that these ranges areintended to be merely illustrative of the preferred embodiment; in somecases higher or lower frequencies may be used.

The ultrasound may be pulsed or continuous, but is preferably continuouswhen lower frequencies are used. At very high frequencies, pulsedapplication will generally be preferred so as to enable dissipation ofgenerated heat.

The preferred intensity of the applied ultrasound is less than about 5.0W/cm², more preferably is in the range of about 0.1 to 5.0 W/cm², andmost preferably is in the range of 0.05 to 3.0 W/cm². The totaltreatment time, i.e., the period over which drug and ultrasound areadministered, will vary depending on the drug administered, the diseaseor injury treated, etc., but will generally be on the order of about 30seconds to 60 minutes, preferably 5 to 45 minutes, more preferably 5 to30 minutes, and most preferably 5 to 10 minutes. It should be noted thatthe aforementioned ranges represent suggested, or preferred, treatmenttimes, but are not in any way intended to be limiting. Longer or shortertimes may be possible and in some cases desirable. Virtually any type ofdevice may be used to administer the ultrasound, providing that thedevice is capable of producing the higher frequency ultrasound wavesrequired by the present method. A device will typically have a powersource such as a small battery, a transducer, a reservoir in which thedrug medium is housed (and which may or may not be refillable), and ameans to attach the system to the desired skin site.

As ultrasound does not transmit will in air, a liquid medium isgenerally needed to efficiently and rapidly transmit ultrasound betweenthe ultrasound applicator and the skin. As explained by P. Tyle et al.,cited above, the selected drug medium should contain a "coupling" or"contacting" agent typically used in conjunction with ultrasound. Thecoupling agent should have an absorption coefficient similar to that ofwater, and furthermore be nonstaining, nonirritating to the skin, andslow drying. It is clearly preferred that the coupling agent retain apaste or gel consistency during the time period of ultrasoundadministration so that contact is maintained between the ultrasoundsource and the skin. Examples of preferred coupling agents are mixturesof mineral oil and glycerine and propylene glycol, oil/water emulsions,and a water-based gel. A solid-state, non-crystalline polymeric filmhaving the above-mentioned characteristics may also be used. The drugmedium may also contain a carrier or vehicle, as defined alone.

A transdermal patch as well known in the art may be used in conjunctionwith the present invention, i.e., to deliver the drug medium to theskin. The "patch", however, must have the properties of the couplingagent as described in the preceding paragraph so as to enabletransmission of the ultrasound from the applicator, through the patch,to the skin.

As noted earlier in this section, virtually any chemical material orcompound suitable for transdermal, transmucosal or topicaladministration may be administered using the present method. Again, thepresent invention is particularly useful to enhance delivery ofproteinaceous and other high molecular weight drugs.

The method of the invention is preferably carried out as follows. Thedrug medium, i.e., containing the selected drug or drugs in conjunctionwith the coupling agent and optionally a carrier or vehicle material, isapplied to an area of intact body surface. Ultrasound preferably havinga frequency greater than about 10 MHz may be applied before or afterapplication of the drug medium, but is preferably applied immediatelybefore application of the drug so as to "pretreat" the skin prior todrug administration.

It should also be pointed out that the present method may be used inconjunction with a chemical permeation enhancer as known in the art,wherein the ultrasound enables the use of much lower concentrations ofpermeation enhancer--thus minimizing skin irritation and other problemsfrequently associated with such compounds--than would be possible in theabsence of ultrasound. The permeation enhancer may be incorporated intothe drug medium or it may be applied in a conventional transdermal patchafter pretreatment of the body surface with ultrasound.

The present invention may also be used in conjunction with iontophoresisfor drugs which are particularly difficult to administer through theskin, i.e., because of the low permeability of the stratum corneum tosuch drugs. The selected area of the body surface is pretreated withultrasound and the drug is then administered using conventionaliontophoresis techniques.

With respect to skin location, virtually any area of the body surfacemay be selected so long as it is intact, however, the thickness andpermeability of skin at the site of exposure will affect the treatmentconditions, i.e., intensity, frequency, contact time, exposure time, andthe like. The area of skin through which the drug medium and theultrasound will be administered can again vary greatly, but willtypically be on the order of 1 to 100 cm², more typically on the orderof 50 to 100 cm², most typically on the order of 10 to 50 cm².

EXAMPLE

Based on the present inventors' theoretical analysis of the propagationof ultrasound energy in tissue and the barrier properties of skin, itwas concluded that higher ultrasound frequencies might be more effectivein enhancing the flux of drug molecules across the skin. Thisconclusion, based on the assumption that enhancement is proportional tothe amount of energy dissipation within the barrier, is supported byFIG. 1, which suggests that, within the first millimeter of skin,ultrasound energy dissipation increases exponentially with frequency.

To test the hypothesis that higher frequencies (>10 MHz) would yieldgreater enhancement, in vivo experiments were performed on hairlessguinea pigs. The setup for carrying out the experiment consisted of afunction generator, transducers tuned at different frequencies and apower-meter. ¹⁴ C-labeled salicylic acid was used as the "model" markerdrug molecule. A saturated solution of unlabeled salicylic acid in waterwas prepared. Carbopol™ (B. F. Goodrich), a polymer, was added to thissolution to make a gel containing salicylic acid at a concentration of0.57% w/w. This gel was then spiked with a known amount of radiolabeledsalicylic acid (approx. 2.27 μCi/mg gel). Approximately 30 mg gel persquare centimeter of transducer cross-sectional area was then applied tothe skin surface of the guinea pigs' flanks. This gel served as both thedrug reservoir and the coupling medium between the transducer and skinsurface. Frequencies of 1, 7.5 and 16 MHz were tested using an intensityof 0.25 W/cm² and treatment periods (time of exposure of the skin toboth drug and ultrasound) of 10 and 20 minutes. At the treatment site,the transducer delivered ultrasound at the appropriate frequency for thedesignated period. At the control site, in the contralateral flank, thetransducer was positioned on the skin, but not activated. Thus, eachanimal served as its own control.

Enhancement was quantified in two ways: (1) by tape-stripping the outerskin layer at the treatment and control sites immediately after theexperimental period (radioactivity in the tape strips was thendetermined by liquid scintillation counting); and (2) by measuring thecumulative amount of ¹⁴ C excreted in the animals' urine up to 14 hoursafter initiation of the experiment.

(1) Tape-strip procedure: It has been established that the uppermostlayer of skin, the stratum corneum (SC), offers the most resistance todrug penetration. Hence, it was decided to compare the amount ofradioactivity present in the SC after ultrasound treatment with thatafter the control experiment (passive diffusion, no ultrasound). FIGS.2, 3 and 4 present a comparison of the total amount of salicylic acidthat had penetrated into the SC with 1, 7.5 and 16 MHz exposure for 20minutes and without exposure to ultrasound. As can be seen, use of 16MHz resulted in a significantly elevated drug level in the SC ascompared to the control. FIGS. 5 and 6 are comparable to FIGS. 3 and 4,but here the treatment time was 10 minutes, rather than 20 minutes. Eachtape strip removed a certain amount of the SC. Hence, with increasingtape-strip number, tissue further away from the surface was examined.Therefore, a plot of the amount of drug in each strip against stripnumber reflects the concentration gradient of drug in the SC. Such plotsare shown in FIGS. 7, 8, 9 and 10. The ordinate is the ratio of theamount of radioactivity in the tape-strip after treatment to the amountin the strip after control.

(2) Urinary excretion: To confirm that the amount of drug recovered fromthe SC reflected the amount of drug penetrated, radioactivity excretedin the urine was monitored. FIG. 1 graphically illustrates a comparisonof the total amount of radioactivity excreted in urine 14 hours after a20 minute treatment using 16 MHz and the corresponding control. At leastfive times more drug entered the system c circulation with ultrasoundthan without.

While the present invention has been described with reference tospecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit of the scope of theinvention. In addition, many modifications may be made to adapt aparticular ultrasound device, drug, excipient material, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

We claim:
 1. A method for increasing the permeability of the stratumcorneum comprising the steps of:(a) applying to an area of the stratumcorneum a material which allows for the transmission of ultrasound; and(b) applying ultrasound to the material wherein the ultrasound appliedhas a frequency of above 10 MHz and is applied at an intensity and for aperiod of time effective to increase the permeability of the stratumcorneum.
 2. The method of claim 1, wherein said ultrasound frequency isin the range of about 15 MHz to 50 MHz.
 3. The method of claim 2,wherein said ultrasound frequency is in the range of about 15 to 25 MHz.4. The method of claim 1, wherein said period of time is in the range ofabout 5 to 45 minutes.
 5. The method of claim 4, wherein said period oftime is in the range of about 5 to 30 minutes.
 6. The method of claim 1,wherein said period of time is less than about 10 minutes.
 7. The methodof claim 1, wherein said intensity of said ultrasound is less than about5.0 W/cm².
 8. The method of claim 7, wherein said intensity of saidultrasound is in the range of about 0.01 to 5.0 W/cm².
 9. The method ofclaim 8, wherein said intensity of said ultrasound is in the range ofabout 0.05 to 3.0 W/cm².
 10. The method of claim 1, wherein said area ofthe stratum corneum is in the range of about 1 to 100 cm².
 11. Themethod of claim 10, wherein said area of the stratum corneum is in therange of about 5 to 100 cm².
 12. The method of claim 11, wherein saidarea of the stratum corneum is in the range of about 10 to 50 cm². 13.The method of claim 1 wherein material which allows for the transmissionof ultrasound is a polymer or a gel.
 14. The method of claim 13 whereinsaid material which allows for the transmission of ultrasound furthercomprises a chemical permeation enhancer.
 15. The method of claim 1wherein said material which allows for the transmission of ultrasound isselected from the group consisting of glycerin, water, and propyleneglycol.
 16. The method of claim 1, wherein steps (a) and (b) are carriedout approximately simultaneously.
 17. The method of claim 1, whereinstep (b) is carried out before step (a).
 18. The method of claim 1,wherein step (a) is carried out before step (b).
 19. The method of claim1, wherein the ultrasound is applied continuously.
 20. The method ofclaim 1, wherein the ultrasound is pulsed.